Distribution of bone mineral content is associated with body weight

and exercise capacity in patients with Chronic Obstructive Pulmonary

Disease

Yoshi 五rmi Yamamoto ， Masanori Yoshikawa ， Koichi Tomoda ， Yukio Fujita ， Motoo

Yamauchi ， Ats 凶iko Fukuoka ， Shi 吋iT，副naki ，N oriko Koyama ， Hiroshi Kimura.

SecondDepa 巾nent ofIntemal Medicine ， Nara Medical University ， Nara ， Japan

This study was partly supported by a grant to the Respiratory Failure Research Group

仕omthe Minis 仕yofHealth ， Labour and Welfare ， Japan.

Address for co町espondence: Masanori Yoshikawa ， MD， PhD

Second Depar 加lent of Intemal Medicine ， Nara Medical University ，

840 Shijo-cho ， Kashihara ， Nara 634-8522 ， Japan

Phone: +81-744-22-3051 ， Fax:+81-744-29 閏0907

E-mail: noriy@naramed 同u.ac.JP

Running title: Distribution ofbone mineral content in patients with COPD

Key words: bone mineral content; COPD; body mass index; exercise capacity

1

Abstract

Background: A1though low bone mineral density (BMD) is脳出yprevalent in patients

with chronic obstructive pulmon 町ydisease (COPD) ， the distribution of the reduced

bone mass has not been fully elucidated.

Objectives: To determine the regional bone mass loss and investigate whether the

change in distribution may be associated with body weight loss and functional capacity.

Methods: Body mass index (BMI) was assessed and height squared indices were

derived for the bone mineral content index (BMCI) of the arms ， legs ， and trunk by dual

energy X-ray absorptiometry in 45 male patients with COPD and 12 age- and sex-

matched con 仕01 subjects. Pulmonary function tests were performed and maximal

oxygen uptake (V0 2max) was measured.

Results: The BMCI was lower in the total bone ， legs ， and 仕旧lkof patients with COPD

than in control subjects ， although the BMCI in the arms was similar between the groups.

BMI correlated significantly with the BMCI in all 3 segments. Bone mineral content

(BMC) in 血etrunk expressed as a percentage of to旬1BMC (BMC trunk/ total BMC)

correlated significantly with BMI. The BMCI in the 仕阻止 was c10sely related with

V02max ， but not with airflow limitation.

Conclusions: There was a regional difference in BMC reduction ， but a predominant

reduction of bone ma:ss in the 佐町立 was not associated with the severity of airflow

limitation but rather with body weight loss and exercise intolerance. These data suggest

that body weight loss and exercise intolerance are important risk factors of vertebral

fracture in patients with COPD. (248 wards)

2

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by a usua l1y

progressive airflow limitation 也前 is not ful1y reversible 1). COPD has been recognized

as a systemic disease with ex仕apulmonary manifestations such as cachexia ， skeletal

muscle wasting ， cardiovascular disease ， metabolic s戸ldrome ，and depressio~).

Moreover ， patients with COPD are 剖 ahigher risk of developing osteoporosis than are

healthy subjects 3). Osteoporotic 企actures remarkably reduce quality of life and are

associated with mortality4). In addition ， pu1monary function impairme 凶 caused by

vertebral 企actures is an important problem in patients with COPD 5).

Osteoporosis is a systemic skeletal disease characterized by low bone mineral

density (BMD) and microarchitectural changes in bone tissue th剖 increases an

individual's susceptibility to 企actures 6). The World Health Organization definition of

osteoporosis is based on BMD meas 田ements 7). Dual energy X-ray absorptiome 位y

(DXA) is the gold standard for taking these measurements 8). Osteopenia is defmed as a

BMD 由叫 1-2.5 standard deviations (SDs) below the mean for young ad叫ts (i.e. ， the

T田score) ，whi1e osteoporosis is defined as a BMD > 2.5 SDs be10w the mean for young

adults 7). Many studies have demonstrated lower BMD in patients with COPD 9)10)11)12).

Multiple sites can be used to measure BMD by DXA. The sites most 仕equently

used are the hip ， lumbar spine ， forearm and whole body. The Intemational Society for

Clinical Densitometry advocates measurement of BMD of the lumb 訂 spine and the hip

and to base the diagnosis of osteoporosis on the lowest T-score of the measured

locations 13). Indeed ， a higher prevalence of osteoporosis was found using local (hip and

l山由町 spine) compared to whole body DXA scanning in patients with clinica l1y stable

3

COPD I4). Accordingly ， we hypothesize th抗 nu仕itional status ， airflow limitation ， and

exercise capacity would have different effects on bone mass 血 each subregion ，

inc1uding the arms ， legs ， and trunk.

Our objectives were to determine the di抑 ibution of reductions in bone mineral

content (BMC) as a measurement of bone mass and investigate whether the BMC

distribution is associated with body weight loss and maximal exercise capacity.

Materials and methods

Subjects

We enrolled 45 male outpatients with COPD diagnosed according to the definition

of the Global Initiative for Chronic Obstructive Lung Disease (GOLD)I) and 12 age 酬

matched male control subjects. Female p抗ients were not inc1uded in this study because

of their remarkable differences from male patients in the prevalence of osteoporosis and

bone metabolism. In addition ， subjects were exc1uded 企om the study if they were

receiving oral corticosteroid therapy ， or had known heart disease ， malignancy ， cor

pu1monale ， or any other inflammatory or metabolic condition. All subjects gave written ，

informed consent and the study had local research ethics committee approva 1.

Pulmonary function tests

All patients underwent pulmonary function testing. Vital capacity (VC) ， forced

vital capacity (FVC) ， forced expiratory volume in one second (FEV 1)， residual volume

(RV) and totallung capacity (TLC) were measured by a pulmon 紅 yfunction instrument

using computer processing (FUDAC 70; Fukuda Denshi ， Tokyo ， Japan) and the

FEV llFVC ratio was calculated. Lung volumes were determined by the helium gas

4

dilution me出od and diffusing capacity for carbon monoxide (DLco) was measured by

the single-breath method. The values obtained were expressed as a percentage of the

predicted values 15). Art erial blood samples obtained in room air were analyzed by a

standard blood gas analyzer (ABL800; Radiometer Corp. ， Copenhagen ， Denm ぽk).

Body mass inde 玄and body composition analysis

Body mass index (BMI) was calculated as weight /height squ 訂ed. BMC and

fat- 企eemass (FFM) we問 measured by DXA using a total body scanner (Lunar DPX;

Lunar Radiation Corp. ， Madison ， WI， USA). BMC and FFM in the subregions ，

inc1uding the trunk ， arms ， and legs can be determined separately or together as a whole

body. Height squared indices were derived for BMC (BMCI) and fat 間企ee mass index

(FFMI) of the arms ， legs ， and trunk. BMC in each subregion expressed as a percentage

oftotal B乱1C，BMC arms/total BMC ， BMC legs/total BMC and BMC trunk/ total BMC

was defined as the BMC dis 凶bution.

Exer cIse performance

All patients underwent maximal exercise tests on a cycle ergometer (STB -1350;

Nihon Kohden ， Tokyo ， Japan). After 1 min of unloaded pedaling ， the wor k1oad was

increased by 10 W every minute in a ramp protocol until exhaustion. Gas exchange was

monitored during 血eexercise test with a computerized metabolic cart (Vmax 229 ，

SensorMedics Corp. ，Yorba Linda ， CA， USA). Minute ventilation (VE) ， oxygen uptake

(Vo 2)， and carbon dioxide outp 叫 (VC02) were measured by the breath-by-breath

method. Art erial oxygen saturation was also monitored by a pulse oximeter (BSM-8500;

Nihon Kohden ， Tokyo ， Japan).

5

Statistical analysis

Values are expressed as means + SD. The differences among measured parameters

in the two groups were determined by unpaired Student's t tests. Pearson's correlation

coefficients among static lung function ラbody composition measurements and V 02max

were calculated. Differences of pく0.05 were considered statistically significan t.

Results

Anthropometric and pulmonary function data

The study was conducted from November 2011 to December 2012. Patient

characteristics are summarized in Table 1. There was no difference in age between the

control and patient groups (71 +6 vs. 70+6 yr). BMI was significantly lower in the

patient group than in the controls (18.5 士2.6 vs. 22.3 + 1.9 kg/m 2， p<O.OOOI). There was

no difference in smoking status between the two groups. FEV 1 % predicted ， FEV l/FVC

ratio and VC % predicted were significan t1y lower in the patient group than in the

control group (45 .4+22.5 vs. 93.0+3.9 %， 41.4+ 12.2 vs. 84.0+2.3 %， 84.5 土21.3vs.

95.7+2.0 %， p<O.OOOI).

Body composition analysis

The BMCI and FFMI values of the patients and the control subjects for both the

total and the subregions are shown in Table 2. Total BMCI and FFMI values of the

patients were significan t1y lower than those of the controls 旬<0.01 and p<O.OI ，

respectively). BMCI in the legs and trunk were significantly reduced in the patients

comp 訂ed with the control subjects 句<0.05 and p<0.05 ， respectively). However ， there

6

was no significant difference in arm BMCI between the two groups (Figure 1). In

contrast ， the FFMI in the aロns and trunk was significantly lower in the patients than in

the control subjects (p<0.05 and p<0.005 ， respectively) and there was no significant

difference in FFM in the legs between the two groups. In addition ， there was a

significant relationship between total BMCI and total FFMI in patients with COPD

(r=0 .418， p<0.005).

Correlations between BMC and BMI in patients with COPD

Total and subregion BMCI correlated significantly with BMI (Table 3). BMC

tru nk/ total BMC correlated significantly with BMI (Figure 2)， whereas BMC arms/total

BMC and BMC legs/total BMC did not correlate with BMI.

Correlation be何 een BMC and functional capacity

Total and each subregion BMCI did not correlate with FEV 1% predicted. In

addition ， the distribution of BMC did not correlate with FEV 1% predicted (Table 3).

Total BMCI did not correlate with other pulmonary function parameters ， including %

RV， Pa02 and PaC0 2 but 出dcorrelate %DLco (r=0.339 ， p<0.05) (data not shown).

Total and subregion BMCI correlated significantly with V02max (Table 3). BMC trm 吐U

total BMC correlated significantly with Vo2max 旬=0.0099) ，whi1e BMC arms/total

BMC and BMC legs/total BMC did not correlate with V02max.

Discussion

In the present study ， we found that BMCI was lower in the whole body ， legs ， and

trunk in p瓜ients with COPD than in control subjects ， although BMCI in the arms was

7

sim i1ar between groups. In addition ， BMCI in each subregion correlated significantly

with BMI ， while only the ratio of trunl 王BMC to total BMC correlated significantly with

BMI. We also demonstrated that BMCI was not significantly correlated with the

severity of airflow limitation but was correlated with maximal exercise performance.

Multiple sites ， including the hip ， lumbar spine ， forearm and whole bod ぁcan be

used to measure BMD by DXA and significant differences among various skeletal sites

have been found in patients with osteoporosis 16). A recent study demonstrated that BMD

of the hip and lumbar spine may be more sensitive than whole body BMD for the

diagnosis of osteoporosis in patients with COPD 14). However ， BMD of the upper

extremities was not evaluated in that study.

We found that BMCI in the am1S of patients with COPD was comparable to that of

control subjects ， while BMCI was lower in the whole bod ぁlegs and trunk in patients

with COPD. Although the mechanism of BMC preservation in the arms is unclear ， a

possible explanation may be mechanical stresses on the bones in the arms in daily life.

The metabolic and vent i1atory requirements as well as dyspnea during unsupported aロn

exercise are greater in patients with COPD than in healthy subjects 17). However ， the

aロns are recruited for many activities of daily living such as lifting ， bathing ， and

dressing for patients with COPD as well as healthy subjects ， whereas patients with

COPD tend to refrain from walking and standing in daily life 18).

Previous studies have demonstrated that a lower BMD is associated with low

BMI ll)19)20)21). However ， a relationship between regional change in B孔1C and BMI has

not been examined. Our data demonstrated that BMCI in each subregion correlated

significan t1y with BMI as well as total BMC I. In particular ， BMCI in the trunk was

cIosely related with BMI compared with that in the aロns and legs. With regard to the

8

distribution of BMC reduction ， BMC 佐山武/tota1 BMC corre1ated significantly with

BMI ， whi1e BMC arms/tota1 BMC and BMC 1egs/tota1 BMC did not. A high preva1ence

of vertebra1 企acture in patients with COPD has been documented 22)23)24)25). The risk of

vertebra1 仕actures is re1ated to disease severity 23)24) and systemic corticosteroid use 22)23).

Our data suggest that body weight 10ss 1eads to a disproportiona1 decrease in BMC in

the trunk and raises the possibility that vertebra1 企actures may be common in

underweight patients with COPD. It is known that the bones in the trunk ， including the

vertebrae and ribs ， predominantly consist of cancellous bone which exerts enhanced

bone metabolism. Thus ， BMC in the 仕阻止may be more susceptib1e to ma1nu 仕ition than

也atin血eextremities.

The deterioration of the microarchitecture and bone remodeling is a1so an

important risk factor of bone 企actures in patients wi血 COPD. Microarchitectura1

changes can be assessed by histomorphome 仕ic ana1ysis or micro-computed

tomographic ana1ysis ofbone biopsy samp1es 26)， which 町etoo invasive to be considered

in a routine clinica1 setting. Therefore ， these ana1yses were not perfo ロned in the present

study. Bone turnover markers represent bone remodeling and are commonly used as

independent predictors of企acture risk 27). In patients with COPD ， these markers can be

significant predictors of企actures independent ofBMD ， but we did not determine in the

present study.

Severa1 studies have reported a strong corre1ation between the preva1ence of

osteoporosis and reduced FFM in patients with COPD 23)24)28). In line with these studies ，

a significant corre1ation between tota1 BMCI and tota1 FFMI was found in our study ，

whi1e the dis 廿ibution ofBMC differed from that ofFFM I.

A higher GOLD stage andlor a 10wer FEVl have been shown to be corre1ated with

9

osteoporosis and/or a low BMD 20)29)30). Moreover ， a significant correlation between

FEVl and BMD in subjects without COPD 31)32) has been reported. On the other hand ，

several studies have demonstrated no significant relationship between %FEV 1 and

BMD in patients with COPD 10)25)28)33). These relationships between pulmonary function

parameters and BMD are complex and not yet clear. In the present study ， we found no

Slgnl 臼cant relationship between total or subregional BMCI and %FEVl. However ラ

BMCI was significantly correlated with %DLco in accordance with other studies 34)35).

Reduced physical activity due to impaired pulmonary function may cause

osteoporosiS 36). Patients with COPD have been shown to be physically inactive

compared with age-matched healthy subjects 均. Although an association between

physical activity and BMD in healthy women has been demonstrated 38)39) ラthe effect of

exercise capacity on BMD has not been fully elucidated in patients with COPD. A

significant relationship between osteoporosis and 6-min walk distance was reported in

patients with COPD 25). In a longitudinal stud 弘 the change of total BMC was shown to

be significantly correlated with 12-min wal1王 distance 40). In the present study ， a

significant relationship between BMCI and maximal oxygen uptake was demonstrated.

This result indicated that the reduction ofbone mass was related to exercise intolerance ，

not to the severity of airflow limitation.

Furthermore ， systemic inflammation has been considered a major cause of

osteoporosis in COPD. Several studies have demonstrated that physical inactivity

deteriorates exercise-induced oxygen desaturation 41) and systemic inflammation and

results in higher serum levels of interlekin-6 and tumor necrosis factor 四 α42)43) which

can contribute to osteoporosis 44). These findings suggest that active patients with higher

V02max levels may have lower levels of these cytokines ， resulting in preserved bone

10

mass. In addition ラ V02max is known to be determined by circulatory and ventilatory

capacity and exercise muscle performance. We hypothesize that oxygen delivery to

bone tissue may be better in patients with higher V02max than in those with lower

V02max.

Moreover ， we demonstrated that BMC tru nk/ total BMC correlated significantly

with V02max ， whi1e BMC arms/total BMC and BMC legs/total BMC did not.

Although the precise mechanism is unclear ， several possible explanations for the

significant relationship between BMC trunk/total BMC and V02max can be made. The

effects of cytokines on bone metabolism may differ between the extremities and the

vertebrae. The relationship between cytokine production by peripheral blood

mononu c1ear cel1s and the rate of annual change in BMD has shown significant

differences in the lumbar spine and the femoral neck ， possibly reflecting differences in

the proportion oftrabecular and cortical bone at these sites 45). Accordingly ， we speculate

that inactive patients with systemic inflammation may have lower BMD in the lumbar

spine than in the extremities.

Decreased BMC in the trunk is a risk factor for vertebral fractures which were not

evaluate in the present study. Kyphosis due to vertebral fractures may reduce pulmon ぽy

function and ventilatory capacitl 6). In the prese 凶 study ，BMC trunk/BMC total was

significantly correlated with maximal voluntary vent i1ation ， which is a significant

determinant of Vo2max 47) (data not shown). This may partly explain the significant

relationship between BMC tru nk/ BMC totaland Vo2max.

Our study has several limitations. First ， we did not dete ロnine pulmonary function

parameters ， except for spirometric data and V02 max in the controls. Accordingly ， it is

unknown whether BMCI is significantly correlated with %DLco and V02 max in both

11

patients with COPD and in control subjects. Second ， despite evidence of statistical

significance ， a direct cause-effect relationship between V02 max and BMC trunk/BMC

total could not be established. An interventional study is required that inc1udes exercise

training and/or anti-osteoporotic medication. Third ， our study included a small number

of patients with COPD and control subjects. Therefore ， a future study with a larger

number of subjects is required to validate 0町 findings.

In con c1usion ， the current study demonstrated a regional difference in BMC

reduction in patients with COPD ， and that BMC reduction is not associated with the

severity of airflow limitation but rather with body weight loss and exercise intolerance.

Body weight loss and exercise intolerance are more c10sely related to BMC reduction in

the trunk than in the extremities. These da臼 suggest that weight loss and exercise

intolerance are important risk factors ofvertebral fractures in patients with COPD.

Conflict of interest

All authors acknowledge that there are no conflicts of interest with any

companies/organizations whose products or services may have influenced this study or

manuscrip t.

Acknowledgement

The authors are indebted to Professor J. Patrick Barron ， Chairman of Department

of the Intemational Medical Communications Center of Tokyo Medical University for

his review of this manuscrip t.

12

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20

T耳ble 1 Pa主i組包chl3f act 師事長記事

Char 語cteristics封。

Age ，yr BMI ，kglm: 童

話，moking 量怯.t us( 郎町側出馬%)

Stage (GOLD) ， n 1 II m B

施 Vr%pred.毘 V!IFVC 笠%VC， %pred. 都内工，C，警告DLc:o，号ゆredPaOz ，mm狂喜P畠COz ，mm時V02航海蕊VEm l!X

A器p02

1ゐ1現 Siif' 密組垂韮毘土意D.

COPD 45

70 主 618.5 ま 2.612188

5 11 17 12

45.4:!: 22.5 41.4主 12.284.5:!: 21.3 57.8 ま 10.042.8:!: 23.5 72.2:!: 8.4 44.1 主 5.0593 .4主 2フ3131.7主 10. 量

6.4主 5.1

EおI司Xl dy綴軍基iind 量茸;GOL D=G lぬ韮Hnit 忌t同意)rC 長凶器icObi 草加clIv圭Lmgdis 軍鶴見

FEV ，=お詑話題pi間企庁vol'耳宜謹 i盟関軍事組耳障重;FVC=; 伽t: ed町ilal 抱卵city;VC 司italcapadty;RV: 帯主I血昌1vo1_ 忠弘C=tOI 誼11u 盟gcapacity;DLα Fdi鐙誌除草 E等acity おrcarbon翻倣oxid: 霊;'¥l' c註海軍阿部xi箇E彊車xy悪事毘盟pl故岳町暫定担誠司盟問d題担沼知加盟主宰venti ぬtf岳民&母国:adr 勧告悶u!鞄試み betw ，線路島必r是andafter 路町i鎚桧:ot1Ilg.

21

22

五もle2 BMCI 制 .dFFMIof 腿ibregion 置inCOPDpa t1組.ts and 四 ntrols

BMCI(k ダ胤宜〉 FFMI(k g!m:今

Controls COPD Controis COPD (11=12) (n=45) (n=1 2) (1'1=4 5)

Tot 3!l 0.92 主 0.17 0.79:!: 0.14 輔 17.O:!: 1.6 15.2:!: 1.7##

Ar泊施 0.13 主 0.03 0.11 ぉ0.02 1.69土&弛 1.43:!: 0.354 事

主暑草醤 0.33まな踊 な29主 0.05 本 5.53 主 0.84 5.14 土0.80

す拘置泳 0.26:!: Oj部 な21主 0.06 キ 事.15 烹 0.6 耳 7.21:!: 0.75 !3

VaI:官豊富舷魯 m鵠 a会事D.BMCI= 加臨ml間a1間盟加 t(培 Jheight(m )l; FF1 必=品会舘 mas! (kg) lheight 加予帥 p<O.01. 容p<O.05 ゐr設lediffi 釘偲様inB 泊四bet:腕組問抽出制 .dCOPD.議p<O.05 ，非社メ:o.o1，!3 p<O..o 05fortn 母differ 偲偲i民主将iIT betw 富国間出d世田昌COPD.

Table 3制 ations 泌.p bet¥vl容をmBJ¥.1I滋 :ld functio nal. cap 時慰問dBMC in subfl 告訴由民Sor distr まbution ofBMC

BW %毘V1 V02max

宜 Pヤ昌~U告 r .pv油ぉ r pvalu 阜

BMCI{tota 品 0.4~雪6 0.00 む4 0.176 0.2502 む.414 む.0048

B主主GI{arms) 0.465 O.∞11 0.105 0.4958 0.344 な0217

BMG I{l egs) 0.466 0.0011 0.157 0.3063 0.467 む.0012

BMGI {tru必合 0.542 0.0001 な243 0.1087 。.4 53 0.0018

BMG arm f totru BMG 0.002 0.9916 心.1 99 0.4367 -0‘104 0.5043

BMG leg I totru BMC -0.054 0.7282 -0.0&2 05961 0.120 0.43 99

BMG 蜘 nk/totalB 出C 0.401 0.0059 0.284 0.0584 0.382 0.0099

r: 1泊施。a昔日Of偲Ia!I oncoe 却ci組 t軍制C= b叩岳部i白書ra1corm 岳民捌CI=bo盟問館空白砂ent(kg) Iheight 神世間早もodym 磁器納豆;

FHV1=forc 婦僻句評ifaf: Oty vo1蜘量 lno 雌慨∞.d;VO z臨肝強制加加国yg呈nupt 汰記

23

Figure legends

Figure 1. BMCI in the arms ， legs ， and 仕阻止 in patien 臼 with COPD. BMC=bone

mineral content ， BMCI=bone mineral content index (kglm 2). Values 町emean 土SD of

45 patients with COPD and 12 controls.

Figure 2. Relationship between BMI and BMC trunk/ total BMC. BMI= body mass

index ， BMC 仕unk= bone mineral content in the 佐田1k， total BMC= bone mineral content

in whole body.

24

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